Both placebo and nocebo studies are important research issues with broad implications for human self-healing and self-harming. Placebo analgesia and nocebo hyperalgesia are the most robust placebo and nocebo effects, and these effects provide a unique example of how contextual learning/conditioning can either relieve or aggravate our pain experience. Previous studies have demonstrated that both placebo analgesia and nocebo hyperalgesia derive from highly active neural process involving multiple brain regions and neurotransmitters. Studies also indicate that no single neurobiological mechanism can explain both effects. Thus, the crucial next step is to perform comparative studies of different placebo analgesia effects and ascertain how they differ from nocebo hyperalgesia in order to distinguish the different neural mechanisms underlying these important clinical phenomena. Using an innovative brain imaging technique, this proposed study attempts to address two questions: 1) what are the distinct brain mechanisms of placebo effects due to opioid and non-opioid conditioning? and 2) Does a common brain network mediate expectancy-evoked placebo analgesia and nocebo hyperalgesia? Our mechanistic investigation will compare different pharmacological conditioning paradigms (including opioid and non-opioid conditioning) using an integrated MR-PET system, and different experiential expectancy manipulation paradigms (placebo analgesia and nocebo hyperalgesia) using fMRI. Answering these questions will significantly advance our understanding of placebo/nocebo effects, facilitate the development of new methods to harness (or avoid) these self- healing (or self-harming) capacities, inform us on how previous experiences can consciously (by expectation) and unconsciously (by conditioning) sculpt our brain response, and shed light on our understanding of basic principles of brain function, pain perception, and pain modulation. PUBLIC HEALTH RELEVANCE: Both placebo and nocebo responses have significant clinical implications. The aim of this study is to investigate the brain mechanisms of placebo and nocebo effects to facilitate methods to harness or avoid these self-healing and self-harming capacities, respectively.